O. Langer et al. / Bioorg. Med. Chem. 9 (2001) 677±694
689
147.1 [C, JF-C 11 Hz], 152.9 [C, JF-C 245 Hz]; MS (DCI/
NH+4 ) C16H16FNO4, 323 [M+NH4+]. 15T (threo): Rf
0.45±0.50 (heptane:EtOAc, 50:50); Rt (HPLC A; eluent:
1% (v/v) aq CH3COOH:CH3OH: 40:60; ¯ow rate:
4 mL/min): 5±6 min; rt (HPLC B; eluent: heptane:EtOAc:
85:15; ¯ow rate: 5 mL/min): 9±10 min; 1H N MR
(CD2Cl2, 298.0 K) d 1.22 (d, J 6.0 Hz, 3H), 2.70 (bs, w1/2
11 Hz, 1H), 4.66 (m, 1H), 4.94 (d, J 9.0 Hz, 1H), 5.13 (s,
2H), 6.92 (m, 1H), 7.00±7.15 (b, 2H), 7.30±7.55 (b, 5H);
13C NMR (CD2Cl2, 298.0 K) d 16.6 [CH3], 71.7 [CH2],
76.2 [CH], 88.9 [CH], 114.4 [CH], 116.8 [CH, JF-C
20 Hz], 120.4 [CH, JF-C 7 Hz], 128.1 [CH], 128.7 [CH],
129.0 [CH], 135.3 [C], 136.6 [C], 147.4 [C, JF-C 11 Hz,],
153.4 [C, JF-C 246 Hz]; MS (DCI/NH+4 ) C16H16FNO4,
323 [M+NH+4 ].
was ®ltered. The CH3OH was removed under vacuum
and the aqueous residue made alkaline with NH4OH
(28%) and extracted with EtOAc. After washing with
brine, drying (MgSO4) and concentration to dryness the
crude amine was obtained.
Erythro-2-amino-1-(3-benzyloxy-4-¯uorophenyl)-1-propanol
(16E). The hydrogenation procedure described above
was used with 15E (0.17 g, 0.56 mmol) and yielded after
puri®cation by silica gel ¯ash chromatography (CH2Cl2:
CH3OH:Et3N, 100:0:0.05±95:5:0.05) pure 16E (72 mg,
47% yield) in the form of white crystals: Rf 0.10±0.15
(CH2Cl2:CH3OH:Et3N, 70:30:0.05); rt (HPLC A; elu-
ent: 1% (v/v) aq CH3COOH:CH3OH: 60:40; ¯ow rate:
1
4 mL/min): 11.5±12.5 min; H NMR (CD2Cl2, 298.0 K)
d 0.82 (d, J 6.3 Hz, 3H), 3.00 (b, w1/2 15 Hz, 2H), 3.05
(b, w1/2 10 Hz, 1H), 4.49 (d, J 3.3 Hz, 1H), 5.08 (s, 2H),
6.80 (b, w1/2 15 Hz, 1H), 6.95±7.10 (b, 2H), 7.25±7.50 (b,
5H); 13C NMR (CD2Cl2, 298.0 K) d 17.3 [CH3], 52.5
[CH], 71.6 [CH2], 76.2 [CH], 114.2 [CH], 115.9 [CH, JF-C
19 Hz], 119.6 [CH, JF-C 7 Hz], 128.1 [CH], 128.5 [CH],
128.9 [CH], 137.0 [C], 138.6 [C], 146.7 [C, JF-C 11 Hz],
152.3 [C, JF-C 243 Hz]; MS (DCI/NH+4 ) C16H18FNO2,
276 [M+H+].
Erythro- and threo-1-(5-benzyloxy-2-¯uorophenyl)-2-nitro-
1-propanol (17E/17T). The coupling procedure descri-
bed above was used with 14 (0.53 g, 2.27 mmol) and
yielded after puri®cation by silica gel ¯ash chromato-
graphy (heptane:EtOAc, 96:4±94:6) the crude product
(17E/17T). Semipreparative HPLC was used to separate
the corresponding erythro racemate (17E, rt 11.5±
12.0 min) from the threo racemate (17T, rt 10.5±
11.0 min) [HPLC B; eluent: heptane:EtOAc: 92.5:7.5;
¯ow rate: 5 mL/min]. Concentration of HPLC fractions
to dryness aorded 17E (106 mg, 15% yield) and 15T
(247 mg, 36% yield) in the form of colorless oils: 17E
(erythro): Rf 0.50±0.55 (heptane/EtOAc, 50/50); Rt
(HPLC A; eluent: 1% (v/v) aq CH3COOH:CH3OH:
40:60; ¯ow rate: 4 mL/min): 6±7 min; rt (HPLC B;
eluent: heptane:EtOAc: 92.5:7.5; ¯ow rate: 5 mL/min):
Threo-2-amino-1-(3-benzyloxy-4-¯uorophenyl)-1-propanol
(16T). The hydrogenation procedure described above
was used with 15T (0.39 g, 1.29 mmol) and yielded
after puri®cation by silica gel ¯ash chromatography
(CH2Cl2:CH3OH:Et3N, 100:0:0.05±90:10:0.05) pure 16T
(115 mg, 32% yield) in the form of white crystals: Rf
0.10±0.15 (CH2Cl2:CH3OH:Et3N, 70:30:0.05); rt (HPLC
A; eluent: 1% (v/v) aq CH3COOH:CH3OH: 60:40; ¯ow
rate: 4 mL/min): 11.5±12.5 min; 1H NMR (CD2Cl2,
298.0 K) d 0.95 (d, J 5.7 Hz, 3H), 2.84 (b, w1/2 15 Hz,
2H), 2.90 (b, w1/2 10 Hz, 1H), 4.15 (d, J 5.7 Hz, 1H),
5.10 (s, 2H), 6.86 (b, w1/2 15 Hz, 1H), 6.95±7.10 (b, 2H),
7.25±7.50 (b, 5H); 13C NMR (CD2Cl2, 298.0 K) d 19.9
[CH3], 53.6 [CH], 71.6 [CH2], 78.0 [CH], 114.3 [CH],
116.1 [CH, JF-C 19 Hz], 119.9 [CH, JF-C 6 Hz], 128.1
[CH], 128.5 [CH], 128.9 [CH], 137.0 [C], 139.7 [C], 146.9
[C, JF-C 11 Hz], 152.5 [C, JF-C 243 Hz]; MS (DCI/NH+4 )
C16H18FNO2, 276 [M+H+].
1
11.5±12.0 min; H NMR (CD2Cl2, 298.0 K) d 1.37 (d, J
6.6 Hz, 3H), 3.01 (bd, w1/2 13 Hz, 1H), 4.74 (m, 1H),
5.01 (s, 2H), 5.63 (bs, w1/2 11 Hz, 1H), 6.87 (m, 1H), 6.97
(t, J 9.6 Hz, 1H), 7.12 (dd, J 5.7 & 3.3 Hz, 1H), 6.95±
7.10 (b, 2H), 7.25±7.45 (b, 5H); 13C NMR (CD2Cl2,
298.0 K) d 11.8 [CH3], 68.8 [CH], 71.0 [CH2], 85.6 [CH],
114.1 [CH], 116.2 [CH], 116.4 [CH, JF-C 12 Hz], 127.1
[C, JF-C 14 Hz], 128.0 [CH], 128.4 [CH], 128.9 [CH],
137.1 [C], 154.0 [C, JF-C 237 Hz], 155.6 [C]; MS (DCI/
NH+4 ) C16H16FNO4, 323 [M+NH4+]. 17T (threo): Rf
0.50±0.55 (heptane:EtOAc, 50:50); Rt (HPLC A; eluent:
1% (v/v) aq CH3COOH:CH3OH: 40:60; ¯ow rate:
4 mL/min): 6±7 min; rt (HPLC B; eluent: heptane:
EtOAc: 92.5:7.5; ¯ow rate: 5 mL/min): 10.5±11.0 min;
1H NMR (CD2Cl2, 298.0 K) d 1.29 (d, J 6.6 Hz, 3H),
3.11 (bs, w1/2 12 Hz, 1H), 4.76 (m, 1H), 4.97 (s, 2H), 5.25
(b, w1/2 10 Hz, 1H), 6.89 (m, 1H), 6.95±7.05 (b, 2H),
7.25±7.45 (b, 5H); 13C NMR (CD2Cl2, 298.0 K) d 16.1
[CH3], 70.3 [CH], 71.0 [CH2], 88.3 [CH], 114.3 [CH, JF-C
< 3.0 Hz], 116.7 [CH, JF-C 24 Hz], 117.0 [CH, JF-C
8 Hz], 126.7 [C, JF-C 15 Hz], 128.0 [CH], 128.5 [CH],
128.9 [CH], 137.0 [C], 154.8 [C, JF-C 238 Hz], 155.6 [C];
MS (DCI/NH+4 ) C16H16FNO4, 323 [M+NH4+].
Erythro-2-amino-1-(5-benzyloxy-2-¯uorophenyl)-1-propanol
(18E). The hydrogenation procedure described above
was used with 17E (88 mg, 0.29 mmol) and yielded after
puri®cation by silica gel ¯ash chromatography (CH2Cl2:
CH3OH:Et3N, 100:0:0.05±95:5:0.05) pure 18E (43 mg,
54% yield) in the form of white crystals: Rf 0.15±0.20
(CH2Cl2:CH3OH:Et3N, 70:30:0.05); rt (HPLC A; elu-
ent: 1% (v/v) aq CH3COOH:CH3OH: 60:40; ¯ow rate:
1
4 mL/min): 12.5±13.5 min; H NMR (CD2Cl2, 298.0 K)
d 0.86 (d, J 6.3 Hz, 3H), 2.37 (b, w1/2 20 Hz, 2H), 3.20
(bt, w1/2 10 Hz, 1H), 4.83 (d, J 2.7 Hz, 1H), 5.02 (s, 2H),
6.80 (dd, J 8.4 Hz & 3.6 Hz, 1H), 6.91 (t, J 9.0 Hz, 1H),
7.11 (b, w1/2 10 Hz, 1H), 7.25±7.50 (b, 5H); 13C N MR
(CD2Cl2, 298.0 K) d 17.5 [CH3], 51.1 [CH], 70.9 [CH2],
70.9 [CH], 114.4 [CH, JF-C <5 Hz], 115.0 [CH, JF-C
7 Hz], 115.7 [CH, JF-C 24 Hz], 127.9 [CH], 128.3 [CH],
128.9 [CH], 130.1 [C, JF-C 16 Hz], 137.5 [C], 154.7 [C, JF-C
236 Hz, C], 155.3 [C]; MS (DCI/NH+4 ) C16H18FNO2,
276 [M+H+].
General procedure for the reduction of nitroalcohols. To
a solution of the nitroalcohol (erythro- or threo race-
mate) in CH3OH (20 mL) and aq formic acid (30%, v/v,
1.5 mL), Raney nickel (50% slurry in H2O, 40±50 mg)
was added. The reaction mixture was put under H2 and
stirred at rt until all starting material had been con-
sumed. After removal of hydrogen the reaction mixture